Tolerance is induced in 100% of miniature swine recipients of renal allografts selectively mismatched for class I and treated with a 12 day course of Cyclosporine A perioperatively. Heart transplants across the same MHC barrier are prolonged significantly by the same treatment regimen, but all grafts are eventually rejected. We have therefore examined the response to simultaneous transplantation of both heart and kidney across this class I mismatch and have made the exciting observation that the kidney transplants appear to provide complete protection of the hears from both acute and chronic rejection. Our goal in the current proposal is to determine the basis of this protective phenomenon. Specifically, we shall: 1) Determine whether class I mismatched heart transplants are capable of maintaining the tolerance established by simultaneous transplantation of kidney and heart; 2) Determine the requirements for an intact thymus in the induction/maintenance of tolerance to class I mismatched heart transplants; 3) Examine which kidney-derived cell populations and/or antigens are responsible for induction of tolerance to class I mismatched heart transplants, and attempt to utilize such cells and/or antigens in lace of the kidney for tolerance induction; and 4) Compare in vitro parameters of transplant immunity/tolerance in animals bearing allogeneic heart transplants prolonged by tolerance induction versus Chronic immunosuppression. These studies should have both theoretical implications for our understanding of tolerance induction by primarily vascularized allografts and practical implications with respect to the application of tolerance-inducing regimens to heart transplantation.